Reactome | FXN:NFS1:ISD11:ISCU assembles 2Fe-2S iron-sulfur cluster

FXN:NFS1:ISD11:ISCU assembles 2Fe-2S iron-sulfur cluster

Stable Identifier

R-HSA-1362408

Type

Reaction [omitted]

Species

Homo sapiens

Compartment

mitochondrial matrix

ReviewStatus

5/5

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FXN:NFS1:ISD11:ISCU assembles 2Fe-2S iron-sulfur cluster

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Iron-sulfur clusters are assembled on the scaffold, ISCU. Based on homology with bacterial IscU:IscS complexes (reviewed in Johnson et al. 2005), one molecule of ISCU is bound to each subunit of a NFS1 dimer (Marinoni et al. 2012). A single complex may thus be capable of assembling two 2Fe-2S clusters. Sulfide is provided by desulfuration of cysteine by NFS1:ISD11 (Biederbick et al. 2006, Shi et al. 2009, Tsai and Barondeau 2010). It has been proposed that ferrous iron is delivered by FXN (Gerber et al. 2003, Yoon and Cowan 2003, Schmucker et al. 2011) bound to ISCU (inferred from yeast, Wang and Craig 2008), although more recent studies suggested that FXN functions as an allosteric effector to stimulate sulfide transfer (Tsai et al. 2010). Holo-ISCU (ISCU bound to a newly synthesized 2Fe-2S cluster) transiently interacts with a dedicated HSP70 chaperone system including Mortalin (GRP75) and HSP20 and GLRX5 (GRX5). Electrons supplied by FDX2 (FDX1L) are required (Tong et al. 2003, Cai et al. 2017) and may reduce the sulfur from S0 to S2- (sulfide). NFU1 binds an Fe-S cluster (Tong et al. 2003, inferred from bacteria Yuvaniyama et al. 2000) and, from biochemical studies of bacterial NFU1 homologues, is proposed to be an intermediate Fe-S cluster carrier (Bandyopadhy et al. 2008). Mutations in human NFU1 affect only a subset of Fe-S proteins (Navarro-Sastre et al. 2011).

Literature References

PubMed ID	Title	Journal	Year
12947415	An interaction between frataxin and Isu1/Nfs1 that is crucial for Fe/S cluster synthesis on Isu1 Gerber, J, Mühlenhoff, U, Lill, R	EMBO Rep.	2003
15952888	Structure, function, and formation of biological iron-sulfur clusters Johnson, DC, Dean, DR, Smith, AD, Johnson, MK	Annu. Rev. Biochem.	2005
26016389	The Human Iron-Sulfur Assembly Complex Catalyzes the Synthesis of [2Fe-2S] Clusters on ISCU2 That Can Be Transferred to Acceptor Molecules Fox, NG, Chakrabarti, M, McCormick, SP, Lindahl, PA, Barondeau, DP	Biochemistry	2015
22352884	Effector role reversal during evolution: the case of frataxin in Fe-S cluster biosynthesis Bridwell-Rabb, J, Iannuzzi, C, Pastore, A, Barondeau, DP	Biochemistry	2012
22101253	Both human ferredoxins 1 and 2 and ferredoxin reductase are important for iron-sulfur cluster biogenesis Shi, Y, Ghosh, M, Kovtunovych, G, Crooks, DR, Rouault, TA	Biochim. Biophys. Acta	2012
18339629	A proposed role for the Azotobacter vinelandii NfuA protein as an intermediate iron-sulfur cluster carrier Bandyopadhyay, S, Naik, SG, O'Carroll, IP, Huynh, BH, Dean, DR, Johnson, MK, Dos Santos, PC	J. Biol. Chem.	2008
22077971	A fatal mitochondrial disease is associated with defective NFU1 function in the maturation of a subset of mitochondrial Fe-S proteins Navarro-Sastre, A, Tort, F, Stehling, O, Uzarska, MA, Arranz, JA, Del Toro, M, Labayru, MT, Landa, J, Font, A, Garcia-Villoria, J, Merinero, B, Ugarte, M, Gutierrez-Solana, LG, Campistol, J, Garcia-Cazorla, A, Vaquerizo, J, Riudor, E, Briones, P, Elpeleg, O, Ribes, A, Lill, R	Am. J. Hum. Genet.	2011
18319250	Binding of yeast frataxin to the scaffold for Fe-S cluster biogenesis, Isu Wang, T, Craig, EA	J. Biol. Chem.	2008
17331979	Mitochondrial frataxin interacts with ISD11 of the NFS1/ISCU complex and multiple mitochondrial chaperones Shan, Y, Napoli, E, Cortopassi, G	Hum Mol Genet	2007
21944046	Mutations in iron-sulfur cluster scaffold genes NFU1 and BOLA3 cause a fatal deficiency of multiple respiratory chain and 2-oxoacid dehydrogenase enzymes Cameron, JM, Janer, A, Levandovskiy, V, Mackay, N, Rouault, TA, Tong, WH, Ogilvie, I, Shoubridge, EA, Robinson, BH	Am. J. Hum. Genet.	2011
12970193	Components involved in assembly and dislocation of iron-sulfur clusters on the scaffold protein Isu1p Mühlenhoff, U, Gerber, J, Richhardt, N, Lill, R	EMBO J.	2003
20873749	Human frataxin is an allosteric switch that activates the Fe-S cluster biosynthetic complex Tsai, CL, Barondeau, DP	Biochemistry	2010
12886008	Subcellular compartmentalization of human Nfu, an iron-sulfur cluster scaffold protein, and its ability to assemble a [4Fe-4S] cluster Tong, WH, Jameson, GN, Huynh, BH, Rouault, TA	Proc. Natl. Acad. Sci. U.S.A.	2003
28001042	Human Mitochondrial Ferredoxin 1 (FDX1) and Ferredoxin 2 (FDX2) Both Bind Cysteine Desulfurase and Donate Electrons for Iron-Sulfur Cluster Biosynthesis Cai, K, Tonelli, M, Frederick, RO, Markley, JL	Biochemistry	2017
26016518	Frataxin Accelerates [2Fe-2S] Cluster Formation on the Human Fe-S Assembly Complex Fox, NG, Das, D, Chakrabarti, M, Lindahl, PA, Barondeau, DP	Biochemistry	2015
19454487	Human ISD11 is essential for both iron-sulfur cluster assembly and maintenance of normal cellular iron homeostasis Shi, Y, Ghosh, MC, Tong, WH, Rouault, TA	Hum Mol Genet	2009
12785837	Iron-sulfur cluster biosynthesis. Characterization of frataxin as an iron donor for assembly of [2Fe-2S] clusters in ISU-type proteins Yoon, T, Cowan, JA	J Am Chem Soc	2003
16847322	Role of human mitochondrial Nfs1 in cytosolic iron-sulfur protein biogenesis and iron regulation Biederbick, A, Stehling, O, Rösser, R, Niggemeyer, B, Nakai, Y, Elsässer, HP, Lill, R	Mol. Cell. Biol.	2006
22306468	Interaction of J-protein co-chaperone Jac1 with Fe-S scaffold Isu is indispensable in vivo and conserved in evolution Ciesielski, SJ, Schilke, BA, Osipiuk, J, Bigelow, L, Mulligan, R, Majewska, J, Joachimiak, A, Marszalek, J, Craig, EA, Dutkiewicz, R	J. Mol. Biol.	2012
22511353	(IscS-IscU)2 complex structures provide insights into Fe2S2 biogenesis and transfer Marinoni, EN, de Oliveira, JS, Nicolet, Y, Raulfs, EC, Amara, P, Dean, DR, Fontecilla-Camps, JC	Angew. Chem. Int. Ed. Engl.	2012
10639125	NifS-directed assembly of a transient [2Fe-2S] cluster within the NifU protein Yuvaniyama, P, Agar, JN, Cash, VL, Johnson, MK, Dean, DR	Proc. Natl. Acad. Sci. U.S.A.	2000